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Abstract
BackgroundThe complement system is one of the important contributing factors in the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). C5a and the neutrophil C5a receptor play a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. The current study further investigated the signaling pathways of C5a-mediated priming of human neutrophils for ANCA-induced neutrophil activation.Methodology/Principal FindingsThe effects of the p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190), extracellular signal-regulated kinase (ERK) inhibitor (PD98059), c-Jun N-terminal kinase (JNK) inhibitor (6o) and phosphoinositol 3-kinase (PI3K) inhibitor (LY294002) were tested on respiratory burst and degranulation of C5a-primed neutrophils activated with ANCA, as well as on C5a-induced increase in expression of membrane-bound PR3 (mPR3) on neutrophils. For C5a-primed neutrophils for MPO-ANCA-induced respiratory burst, the mean fluorescence intensity (MFI) value was 254.8±67.1, which decreased to 203.6±60.3, 204.4±36.7, 202.4±49.9 and 188±47.9 upon pre-incubation with SB202190, PD98059, LY294002 and the mixture of above-mentioned three inhibitors (compared with that without inhibitors, P<0.01, P<0.05, P<0.01 and P<0.05), respectively. For PR3-ANCA-positive IgG, the MFI value increased in C5a-primed neutrophils, which decreased upon pre-incubation with above-mentioned inhibitors. The lactoferrin concentration increased in C5a-primed neutrophils induced by MPO or PR3-ANCA-positive IgG supernatant and decreased upon pre-incubation with above-mentioned three inhibitors. mPR3 expression increased from 923.3±182.4 in untreated cells to 1278.3±299.3 after C5a treatment and decreased to 1069.9±188.9, 1100±238.2, 1092.3±231.8 and 1053.9±200.3 by SB202190, PD98059, LY294002 and the mixture of above-mentioned three inhibitors (compared with that without inhibitors, P<0.01, P<0.05, P<0.01 and P<0.01), respectively.Conclusions/SignificanceActivation of p38MAPK, ERK and PI3K are important steps in the translocation of ANCA antigens and C5a-induced activation of neutrophils by ANCA.
Highlights
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA, previously named Wegener’s granulomatosis), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). [1]
Neutrophils were incubated with different concentrations of C5a (10, 100, 500 and 1000 ng/ml), and membrane-bound Proteinase 3 (PR3) (mPR3) expression was determined by flow cytometry
We investigated whether C5a-primed neutrophils for antineutrophil cytoplasmic antibody (ANCA)-induced respiratory burst were dependent on activation of the p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and phosphoinositol 3-kinase (PI3K) pathways
Summary
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA, previously named Wegener’s granulomatosis), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). [1]. Increasing evidences suggest that ANCA-induced neutrophil activation plays an important role in the pathogenesis of AAV. In an anti-MPO antibodyinduced mouse vasculitis model [7], ANCA and neutrophils are necessary for the initiation of glomerulonephritis [7,8] Recent studies, both in the mouse model and in human, suggested that complement activation via the alternative pathway is one of the important contributing factors in the disease development [9,10,11]. The complement system is one of the important contributing factors in the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). C5a and the neutrophil C5a receptor play a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. The current study further investigated the signaling pathways of C5a-mediated priming of human neutrophils for ANCA-induced neutrophil activation
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